Liang Xiaoyan, Mu Min, Chen Bo, Fan Rangrang, Chen Haifeng, Zou Bingwen, Han Bo, Guo Gang
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
Biomater Res. 2023 Nov 24;27(1):120. doi: 10.1186/s40824-023-00447-x.
Triple-negative breast cancer (TNBC) is an aggressive, metastatic and apparently drug-resistant subtype of breast cancer with a higher immune response compared to other types of breast cancer. Photodynamic therapy (PDT) has been gaining popularity for its non-invasive nature, minimal side effects, and spatiotemporally controlled benifits. The use of metal-organic frameworks (MOFs) loaded with programmed death-ligand 1 inhibitors (iPD-L1) offers the possibility of combining PDT with immunotherapy.
Here, we construct PCN-224, a MOFs with good biocompatibility and biodegradability for the delivery of the PD-L1 small molecule inhibitor BMS-202 to achieve a synergistic anti-tumor strategy of PDT and immunotherapy. Hyaluronic acid (HA) modified PEG (HA-PEG) was synthesized for the outer layer modification of the nanocomplex, which prolongs its systemic circulation time.
In vitro cellular experiments show that the nanocomplexes irradiated by 660 nm laser has a strong ability to produce singlet oxygen, which effectively induce PDT. PDT with strong immunogenicity leads to tumor necrosis and apoptosis, and induces immunogenic cell death, which causes tumor cells to release danger associated molecular patterns. In combination with iPD-L1, the combination therapy stimulates dendritic cell maturation, promotes T-cell activation and intratumoral infiltration, and reshapes the tumor immune microenvironment to achieve tumor growth inhibition and anti-distant tumor progression.
MOFs-based nano-systems as a platform for combination therapy offer a potentially effective strategy for the treatment of TNBC with high metastatic rates.
三阴性乳腺癌（TNBC）是一种侵袭性、转移性且明显耐药的乳腺癌亚型，与其他类型的乳腺癌相比，其免疫反应更高。光动力疗法（PDT）因其非侵入性、副作用小以及时空可控的优点而越来越受欢迎。负载程序性死亡配体1抑制剂（iPD-L1）的金属有机框架（MOF）的使用为将PDT与免疫疗法相结合提供了可能性。
在此，我们构建了PCN-224，这是一种具有良好生物相容性和生物降解性的MOF，用于递送PD-L1小分子抑制剂BMS-202，以实现PDT和免疫疗法的协同抗肿瘤策略。合成了透明质酸（HA）修饰的聚乙二醇（HA-PEG）用于纳米复合物的外层修饰，从而延长其全身循环时间。
体外细胞实验表明，经660nm激光照射的纳米复合物具有很强的产生单线态氧的能力，能有效诱导PDT。具有强免疫原性的PDT导致肿瘤坏死和凋亡，并诱导免疫原性细胞死亡，使肿瘤细胞释放危险相关分子模式。与iPD-L1联合使用时，联合疗法刺激树突状细胞成熟，促进T细胞活化和肿瘤内浸润，并重塑肿瘤免疫微环境，以实现肿瘤生长抑制和抗远处肿瘤进展。
基于MOF的纳米系统作为联合治疗的平台，为治疗高转移率的TNBC提供了一种潜在的有效策略。
